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A Bird’s Eye View of Atropisomers Featuring a Five-Membered Ring Damien Bonne, Jean Rodriguez To cite this version: Damien Bonne, Jean Rodriguez. A Bird’s Eye View of Atropisomers Featuring a Five-Membered Ring. European Journal of Organic Chemistry, Wiley-VCH Verlag, 2018, 2018 (20-21), pp.2417 - 2431. 10.1002/ejoc.201800078. hal-01907622 HAL Id: hal-01907622 https://hal.archives-ouvertes.fr/hal-01907622 Submitted on 29 Oct 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. DOI: 10.1002/ejoc.201800078 Microreview Atropisomerism A Bird's Eye View of Atropisomers Featuring a Five-Membered Ring Damien Bonne*[a] and Jean Rodriguez*[a] Abstract: An atropisomer is a member of a subclass of re- chemical bond. After a short introduction, the occurrence of stricted rotational conformers – this restricted rotation giving atropisomers in nature is presented, as well as the synthetic rise to stereogenic sigma bonds – that can be isolated as sepa- efforts – encompassing non-stereoselective and diastereo- rate chemical species. Most atropisomer are six-membered-ring selective strategies, together with an update on very recent biaryl or heterobiaryl derivatives. The aim of this microreview is enantioselective approaches – devoted to such axially chiral to shed light on a less common class of atropisomers, those compounds. Finally, a special focus is placed on their important containing at least one five-membered hetero- or carbocycle utilization as original and efficient ligands for metal complexes. and displaying variously a stereogenic C–N, C–C, or even N–N 1. Introduction N–N bond have received less attention.[6i] This situation is basi- cally due to the increased distance between the ortho-substitu- Nonracemic axially chiral systems of type 1[1] (Scheme 1) are ents (R1 to R4) next to the axis, which is responsible for lower recognized as central elements in many scientific domains, with barriers to rotation, hampering the conformational stability notably numerous applications in catalyst design,[2] drug dis- (Scheme 1). covery,[3] and materials sciences,[4] and are also widely repre- sented in nature. Among them, six-membered carbocyclic – and, to lesser extent, heterocyclic – atropisomers[5] have com- manded huge attention over the years and still constitute a central topic of research worldwide, resulting in the develop- ment of many elegant synthetic approaches.[6] In sharp con- trast, atropisomeric species featuring one or even two five- membered rings connected variously through a C–C, C–N, or [a] Aix Marseille Université, CNRS, Scheme 1. Situation of six- versus five-membered atropisomeric systems. Centrale Marseille, iSm2, France E-mail: [email protected] or [email protected] Pioneering observations and experimental determinations of http://ism2.univ-amu.fr/fr/stereo/stereo ORCID(s) from the author(s) for this article is/are available on the WWW barriers to rotation highlight the crucial effect of ortho-substitu- under https://doi.org/10.1002/ejoc.201800078. ents. It has been proposed by Oki that a pair of atropisomers Damien Bonne was born in Epinal (France) in 1979. After studying chemistry at the Ecole Supérieure de Chimie de Lyon (CPE Lyon, France), he completed his Ph.D. in 2006 under the supervision of Prof. J. Zhu, working on isocyanide-based multicomponent reactions. He then moved to the University of Bristol (UK) to join the group of Prof. V. A. Aggarwal as a postdoctoral associate. Since 2007 he has been working as a “Maître de Conférences” (associate professor) at Aix-Marseille University (France). He passed his habilitation (HDR) in 2015 and his research interests include the development of new organocatalyzed methodologies and their application in stereoselective synthesis. Jean Rodriguez was born in Cieza (Spain) in 1958, and in 1959 his family emigrated to France. After studying chemistry at the University of Aix-Marseille (France), he completed his Ph.D. as a CNRS researcher with Prof. B. Waegell and Prof. P. Brun in 1987. He completed his Habilitation in 1992, also at Marseille, where he is currently Professor and Director of the UMR-CNRS-7313-iSm2. His research interests include the development of multiple bond-forming transformations including domino and multicomponent reactions, and their application in stereoselective organocatalyzed synthesis. In 1998 he was awarded the ACROS prize in Organic Chemistry, in 2009 he was awarded the prize of the Division of Organic Chemistry from the French Chemical Society, and in 2013 he became a “Distinguished Member” of the French Chemical Society. Eur. J. Org. Chem. 2018, 2417–2431 2417 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Microreview should exhibit a minimum energy barrier of 93 kJ mol–1, to en- The first of these families is that of the optically pure poly- sure a half-life of at least 1000 seconds at room temperature[7] brominated biindoles 2 from marine blue-green alga Rivularia and to offer reasonable expectation of the convenient separa- firma, isolated in 1982 and including the four C–C-bonded con- tion of the two enantiomeric atropisomers.[8] geners 2a–d and the two C–N-bonded congeners 2e and 2f In this context, the aim of this microreview, after a brief his- (Scheme 2a).[9] torical background highlighting their natural occurrence, is to Another C–N-bonded carbazole alkaloid family, named give an overview on the preparation of atropisomers from ne- murrastifolines A (3a), B (3b), and F (3c), was isolated eleven glected pioneering achievements up to more contemporane- years later from the acetone extract of the root of the plant ous selective approaches, including an update on very recent Murraya koenigii (Scheme 2b).[10] From the substitution pattern enantioselective syntheses. The last section is devoted to their of the axially chiral C–N-bonded phenyl ring of murrastifolines A utilization as efficient ligands for metal complexes, followed by and B, lacking any ortho-substituent, rapid rotation at the biaryl their efficient utilization as ligands for metal complexes. axis was suspected, whereas murrastifoline F, bearing four ortho-substituents next to the axis, was expected to be configu- rationally stable. This was established by Bringmann and collab- 2. In Nature orators in 2001, both through a very high calculated (AM1) atropisomerization barrier of 165 kJ mol–1 and by the unique Both axially chiral C–C- and C–N-bonded atropisomers contain- total synthesis of the F analogue, showing its presence in the ing five-membered rings exist in nature, essentially in three root extract as a 56:44 mixture in favor of the M enantiomer.[11] small, rare families featuring one or two five-membered rings from the indole, carbazole, or pyrrole series. However, their iso- More recently, the two new axially chiral metabolites lation and characterization were achieved only at the end of (–)-marinopyrrole A (4a) and (–)-marinopyrrole B (4b) were iso- the last century (Scheme 2). lated after cultivation of an obligate marine Streptomyces strain[12] and showed potent antibiotic activities against methicillin-resistant staphylococcus aureus (Scheme 2c).[13] Two years after their isolation, two different total syntheses of (±)-marinopyrrole A were reported contemporaneously by the groups of Li[12c] and Sarli,[12d] with nine steps and 30 % yield and six steps and 22 % yield, respectively. 2. Non-Stereoselective Syntheses The first synthesis of an axially chiral five-membered-ring com- pound was that of C–N-bonded[14] arylpyrrole 5a, reported back in 1931 by the group of Adams,[15] followed by a series of pa- pers dealing with the preparation of the related arylcarb- azole[16] 5b and the dipyrryl biphenyl 6[17] (Scheme 3). In all these studies, the racemic atropisomers obtained from the re- quired 1,5-diketones and anilines in a Paal–Knorr heterocycliza- tion in the case of 5a and 6 or through the Ullman-type cou- pling of o-iodobenzoic acid with 3-nitrocarbazole in that of 5b were resolved by means of the corresponding brucine salts. In- terestingly, for pyrrole 5a and carbazole 5b the two enantio- mers were found to be relatively stable in boiling ethanol but to undergo total thermal racemization in the presence of NaOH. Scheme 2. Naturally occurring C–C- and C–N-bonded axially chiral arylazoles. Scheme 3. First families of axially chiral N-arylpyrroles 5 and 6. Eur. J. Org. Chem. 2018, 2417–2431 www.eurjoc.org 2418 © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Microreview After these pioneering contributions, the experimental deter- also demonstrated the possibility of forming a rather stable mination of steric barriers in atropisomers containing five-mem- 12-membered-ring diether atropisomer with a slightly higher bered rings became a central research domain of early confor- barrier to rotation. mational analysis. This was facilitated by the concomitant devel- This unusual intramolecular hydrogen bond effect was ex- opment of chiral liquid chromatography, allowing efficient sep- ploited four years later by Shimizu's group for the design of arations

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